Kelly J. Baines and Rachel C. West of the Anatomy, Physiology and Pharmacology Department of Auburn University published a thorough review article in Biology of Reproduction (BOR) in 2023 on Sex differences in innate and adaptive immunity and what is known about how these differences impact fetal, placental and maternal health (1). This review is reported by BOR as the most cited in the last two years. It summarizes 213 articles of human clinical studies and studies in animal models on how fetal sex impacts reproductive outcomes. The authors state that while “the studies reviewed are descriptive and correlative (they) deepen understanding of a clear sexual dimorphism of the immune response in pregnancy”. They conclude that it is essential to study the molecular mechanisms of the immune response in a sex-specific way to fully understand the impact of both normal and altered responses on fetal, placental and maternal health. Increased knowledge of the molecular mechanisms will enhance the diagnosis and treatment of conditions that result from fetal sexual differences and prevention of poor outcomes, especially in males.
Since the late eighteenth century reproductive scientists and clinicians have understood that there is a higher rate of stillbirths and mortality in male fetuses and neonates although there is newer study that challenge this statement (2). Reports reveal that more preterm births, spontaneous abortions (miscarriages) and small for gestational age infants occur in males. Mothers with male fetuses have more preeclampsia and gestational diabetes that mothers with female fetuses. The authors begin their review by reminding the reader that differences in male and females begin very soon after fertilization. They cite studies that demonstrate that the male embryo reaches the blastocyst stage earlier than female embryos. Furthermore, it has been reported that male blastocysts have more cells than the female blastocysts. Female embryos and fetuses grow at a more regulated rate then male embryos and fetuses.
A detailed reading of this paper is important to the understanding of the present state of the science in the role of embryonic and fetal sex in pregnancy outcomes. This blog is written to encourage the reader to do just that. It is an important and provocative review. Fetal sex influences the placental immune response and this affects both fetal and maternal health as well as the life-long adult health of offspring. A few highlights of the review are noted here. Male fetuses and neonates develop increased severity of and earlier onset of cardiovascular, metabolic and neurocognitive conditions later in life. Furthermore, maternal undernutrition and stressful situations in gestation increases the development of disease in offspring later in life. These studies are reviewed in detail. Many of the studies reviewed report on placenta. The placenta is of course a fetal derived organ and thus will have the same chromosomes as the fetus, with sex chromosomes contributing to placental function. Articles cited in this review report that male first trimester placentas are enriched in expressed genes related to metabolism and biosynthesis while similar female placentas display increased levels of genes related to immunity and cytokine signaling. They also report on studies of the uterine decidua. Together the studies focus on the maternal-fetal interface. Studies on X-inactivation, maternal and paternal imprinted genes, sex-related differences in hormonal levels, sex differences in cytokine signaling in normal and complicated pregnancy are reviewed and demonstrate that these phenomena impacts pregnancy outcomes. Cytokine dysregulation leads to preeclampsia, preterm birth and fetal neurocognitive impairment. The authors reviewed studies that show marked sex-specific differences in interferon response in Covid infected pregnancies. They discuss numerous studies on lymphocyte cell subpopulations in normal and complicated gestations. These subpopulations include uterine NK cells which are the most abundant in type of lymphocytes in the first trimester decidua around the time of implantation. Studies on HLA antigen expression in gestation reveal that HLA-G, for instance is higher in male fetuses. The authors report on regulatory T cells. Experimental depletion of regulatory T cells reduces the number of male pups suggesting that these T cells are important for the survival of male fetuses. In the absence of infection, maternal levels of Il-10 is significantly higher in mothers with male fetus. Regulatory T cells secrete TGF-β. Placentas of males who delivered preterm demonstrate a decrease in TGF-β. This decrease was not found in placenta of female fetuses. CD4+ T cells express androgen receptors and have been studied in gestation leading to the suggestion that androgen may directly or indirectly influence the function of T cells in a sex-dependent manner. The “take home message” is that “Regulatory T cells are important in maintenance of a tolerant uterine environment and may enable this maintenance in a sexually dimorphic manner”.
This review includes studies on B cells. There are not as many reports on B cells as there are on T cells, however. Clinical studies find that pregnant women have higher IgG levels than non-pregnant women. In the decidua B cells are present in lower numbers that other leucocytes, but, the increase as pregnancy advances.
Articles on the impact of fetal sex on maternal immunity are discussed. The authors state: “During pregnancy there is an adaption of the maternal immune system the allows the protection of the mother and fetus from pathogens but also suppresses the maternal immune system in a way that keeps that fetus from being rejected” which is a long accepted concept. They go on to write that “the male fetus and placenta grow faster and metabolize nutrients faster than the female fetus. Thus, male fetuses do not adapt as well as female fetuses to a compromised intrauterine environment leaving them vulnerable to adverse pregnancy outcomes. Many of these adaptions relate to the immune responses observed in pregnancy at the maternal-fetal interface.”
This review article is very informative and highlights the importance of studying sex dimorphism as it affects fetal development and pregnancy complications and the fetal origin of adult disease. Including fetal sex in studies of pregnancy outcomes, such as loss of the male fetus and late complications such as preterm birth, is essential in future studies. In addition, the sexual phenotype of the fetus is a critical factor in studies of pregnancy complications. This review paper presents 213 articles with findings that should inspire studies of the molecular mechanisms of sexual dimorphism in innate and adaptive immunity impacting fetal, placental and maternal health.
References:
- Baines KJ, West RC. Sex differences in innate and adaptive immunity impact fetal, placental, and maternal health†. Biol Reprod. 2023 Sep 12;109(3):256-270. doi: 10.1093/biolre/ioad072. PMID: 37418168.
- Orzack SH, Stubblefield JW, Akmaev VR, Colls P, Munné S, Scholl T, Steinsaltz D, Zuckerman JE. The human sex ratio from conception to birth. Proc Natl Acad Sci U S A. 2015 Apr 21;112(16):E2102-11. doi: 10.1073/pnas.1416546112. Epub 2015 Mar 30. PMID: 25825766; PMCID: PMC4413259.